Current colorectal cancer screening modalities are not universally acceptable, and, for reasons of cost and low specificity, unlikely to be widely applied. To address the exigent need for further screening strategies, we propose to evaluate a biologically based screening approach that will incorporate a variety of cellular and molecular pathways to neoplasia. The focus of this project-and the entire P01- is on oxidative damage and apoptosis. Additionally, several pathways that are unique to colorectal carcinogenesis will be evaluated as possible targets for early detection efforts. Both human and animal studies will be conducted. To identify markers that discriminate patients with adenomas, hyperplastic polyps, ulcerative colitis, and adenocarcinomas from healthy controls, we propose to collect a variety of biologic materials (blood, colonic biopsies, primary lesions, rectal brushings, stool) and risk factor information on Group Health Cooperative of Puget Sound patients (n=800) undergoing clinically indicated colonoscopy. Specimens from individuals in each of the diagnostic categories will be evaluated for: specific markers of oxidative damage; aberrations in apoptosis proteins (bcl-2, bcl-x, bax); glutathione and GST expression; hypermethylation of the estrogen receptor gene; abnormalities in cell proliferation (Ki-67); and aspects of cell-cell interaction (connexins and E-cadherin). Analyses will explore the sensitivity and specificity of each of this group of biologically relevant markers that represent several pathways to carcinogens, with the goal of establishing an ensemble of markers that can facilitate the identification of individuals carrying neoplastic and pre-neoplastic lesions. Ultimately, we plan to evaluate the efficacy of screening using these markers in a prospective screening trial, which we will plan for the P01 renewal.